Eaton Molly E, Macías Wendy, Youngs Rachael M, Rajadhyaksha Anjali, Dudman Joshua T, Konradi Christine
Laboratory of Neuroplasticity, McLean Hospital, Harvard Medical School, MRC215, 115 Mill Street Belmont, MA 02478, USA.
Brain Res Mol Brain Res. 2004 Nov 24;131(1-2):65-72. doi: 10.1016/j.molbrainres.2004.08.007.
Dopamine (DA) receptor-mediated signal transduction and gene expression play a central role in many brain disorders from schizophrenia to Parkinson's disease to addiction. While trying to evaluate the role of L-type Ca2+ channels in dopamine D1 receptor-mediated phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB), we found that activation of dopamine D1 receptors alters the properties of L-type Ca2+ channel inhibitors and turns them into facilitators of Ca2+ influx. In D1 receptor-stimulated neurons, L-type Ca2+ channel blockers promote cytosolic Ca2+ accumulation. This leads to the activation of a molecular signal transduction pathway and CREB phosphorylation. In the absence of dopamine receptor stimulation, L-type Ca2+ channel blockers inhibit CREB phosphorylation. The effect of dopamine on L-type Ca2+ channel blockers is dependent on protein kinase A (PKA), suggesting that protein phosphorylation plays a role in this phenomenon. Because of the adverse effect of activated dopamine receptors on L-type Ca2+ channel blocker action, the role of L-type Ca2+ channels in the dopamine D1 receptor signal transduction pathway cannot be assessed with pharmacological tools. However, with antisense technology, we demonstrate that L-type Ca2+ channels contribute to D1 receptor-mediated CREB phosphorylation. We conclude that the D1 receptor signal transduction pathway depends on L-type Ca2+ channels to mediate CREB phosphorylation.
多巴胺（DA）受体介导的信号转导和基因表达在从精神分裂症到帕金森病再到成瘾等多种脑部疾病中起着核心作用。在试图评估L型Ca2+通道在多巴胺D1受体介导的转录因子环磷酸腺苷反应元件结合蛋白（CREB）磷酸化中的作用时，我们发现多巴胺D1受体的激活改变了L型Ca2+通道抑制剂的特性，并将它们转变为Ca2+内流的促进剂。在D1受体刺激的神经元中，L型Ca2+通道阻滞剂促进胞质Ca2+积累。这导致分子信号转导途径的激活和CREB磷酸化。在没有多巴胺受体刺激的情况下，L型Ca2+通道阻滞剂抑制CREB磷酸化。多巴胺对L型Ca2+通道阻滞剂的作用依赖于蛋白激酶A（PKA），表明蛋白磷酸化在这一现象中起作用。由于激活的多巴胺受体对L型Ca2+通道阻滞剂作用有不利影响，因此无法用药理学工具评估L型Ca2+通道在多巴胺D1受体信号转导途径中的作用。然而，利用反义技术，我们证明L型Ca2+通道有助于D1受体介导的CREB磷酸化。我们得出结论，D1受体信号转导途径依赖于L型Ca2+通道来介导CREB磷酸化。
